The goal of this proposal is to establish a genetic profile of neuronal excitability as it relates to psychostimulant addiction. To accomplish this aim we will be using the most advanced oligonucleotide high density microarray technology combined with patch-clamp electrophysiology. Affymetrix Gene Chips allow for genome wide scans of the entire mouse genome for genes susceptible to chronic psychostimulant administration. In order to understand neural information procession in the brain reward circuitry as it relates to addiction, it is necessary to understand how individual neurons within this system code reward-related information. This project uses both DNA microarrays and patch-clamp electrophysiology to establish a molecular and functional characterization of nucleus accumbens, prefrontal cortical pyramidal neurons and ventral subicular hippocampal pyramidal neurons after repeated psychomotor stimulant injections in rats and mice. Specific aim 1 is to look for voltage and ligand-gated ion-channel genes that are subject to modulation by psychostimulants in the accumbens, subiculum and prefrontal cortical neurons. Specific aim 2 is to determine the functional manifestations of those changes within each structure. Specific aim 3 involves individual neuron gene expression profiling of electrophysiologically classified neurons (e.g. Interneurons and pyramidal bursting and nonbursting). Together these experiments will help us understand how drugs of abuse induce long-lasting neuroadaptations within the brain reward circuitry. With greater understanding of addiction-associated plasticity it may be possible to develop pharmacological or gene profiling strategies to screen for addiction vulnerability and possible therapeutic interventions.